The overall goal of this project is to develop a greater understanding of the interaction of ultrasound with cardiovascular tissues containing gas-based ultrasound contrast agents. The role of ultrasound contrast agents in diagnostic imaging is increasing. However, ultrasound exposure of various tissues containing contrast agents can produce damage to blood vessels. Also, a single pulse of ultrasound can produce effects on cardiac function, such as the production of a premature cardiac contraction and effects on cardiac contractility. The presence of contrast agents in the blood can reduce the threshold for premature cardiac contractions, such that current output levels of diagnostic devices are capable of producing the effect. The proposed project is focused on investigating the effects of ultrasound and contrast agents on cardiac function and vascular damage. An integrated approach is proposed employing both experimental studies and theoretical modeling. Four inter-related specific aims guide the investigations. First, studies to characterize the bioffects of ultrasound on cardiovascular tissues containing contrast will be performed. Thresholds for effects on cardiac function and vessel damage will be determined as a function of acoustic and biological parameters. Second, a theoretical understanding of the response of contrast agents in cardiovascular tissues exposed to ultrasound will be developed. A broad goal of the proposed work is to develop a better understanding of acoustic cavitation in vivo. Techniques will be developed to model acoustic cavitation under conditions relevant to contrast agents contained within the vasculature in vivo. Third, the biophysical mechanisms by which contrast agents enhance bioeffects will be determined. It is hypothesized that ultrasound-induced premature contractions arise from acoustic cavitation and effects on contractility result from radiation force. Studies of vessel damage will be guided by testing two competing hypotheses; that ultrasound induced-damage to blood vessels contain contrast results from 1) phenomena associated with inertial collapse of microbubbles and/or 2) the initial expansion phase of the microbubbles. Fourth, therapeutic uses of ultrasound in cardiovascular tissues will be investigated. The potential use of ultrasound and contrast agents for noninvasive cardiac pacing, defibrillation and electrophysiology procedures will be tested. Results of this project will provide information needed for safety recommendations, will increase the knowledge base of acoustic cavitation in vivo, and will determine the feasibility of potentially new applications of ultrasound and contrast agents in medicine.